JP2011512366A - Folate, their composition and use - Google Patents
Folate, their composition and use Download PDFInfo
- Publication number
- JP2011512366A JP2011512366A JP2010547053A JP2010547053A JP2011512366A JP 2011512366 A JP2011512366 A JP 2011512366A JP 2010547053 A JP2010547053 A JP 2010547053A JP 2010547053 A JP2010547053 A JP 2010547053A JP 2011512366 A JP2011512366 A JP 2011512366A
- Authority
- JP
- Japan
- Prior art keywords
- tetrahydrofolate
- folate
- glucosamine
- methyl
- galactosamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
本発明は、葉酸塩、これらの組成物および使用に関する。特に、本発明は、少なくとも１種の有機塩基の、置換もしくは非置換の葉酸塩もしくは還元型葉酸塩、またはその天然もしくは非天然の異性体である結晶性および非晶性化合物について、ならびにこれらの組成物および使用について記載する。本発明の化合物は、長期持続する安定性および特異的に高い水溶性を示す。 The present invention relates to folate, their compositions and uses. In particular, the present invention relates to crystalline and amorphous compounds that are substituted or unsubstituted folate or reduced folate, or natural or non-natural isomers thereof, of at least one organic base, and these The composition and use are described. The compounds of the present invention exhibit long lasting stability and specifically high water solubility.
Description
本発明は、葉酸塩、これらの組成物および使用に関し、特に、本発明は、少なくとも１種の有機塩基の葉酸塩もしくは還元型葉酸塩のいずれか、またはこれらの天然または非天然の異性体である結晶性および非晶性化合物について、ならびにこれらの組成物および使用について記載する。 The present invention relates to folate, compositions and uses thereof, and in particular, the present invention relates to either folate or reduced folate of at least one organic base, or natural or non-natural isomers thereof. Certain crystalline and amorphous compounds and their compositions and uses are described.
葉酸、すなわち、Ｎ−［４−［［（２−アミノ−１，４−ジヒドロ−４−オキソ−６−プテリジニル）メチル］アミノ］ベンゾイル］−Ｌ−グルタミン酸、およびこのアニオンである葉酸塩は、水溶性ビタミンＢ９の形態であり、ジヒドロおよびテトラヒドロ葉酸の、ならびにこれらの対応するアニオンの前駆体である。これらは、食物中に、主にはその共役体として、特に肝臓、腎臓、イースト、果物および多葉緑色野菜中に天然に存在し、および補助食品としても摂取され得る。市販の葉酸は、この上記の誘導体として、合成により調製されている。 Folic acid, namely N- [4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl) methyl] amino] benzoyl] -L-glutamic acid, and its anion, folate, It is a form of water-soluble vitamin B9, a precursor of dihydro and tetrahydrofolic acid, and their corresponding anions. They occur naturally in food, primarily as conjugates thereof, particularly in the liver, kidneys, yeast, fruits and multileaf green vegetables, and can also be taken as a supplement. Commercially available folic acid is prepared synthetically as this derivative.
葉酸は、黄色または黄橙色の結晶性粉末として存在し、水にきわめて溶けにくく、アルコールには不溶であり、アルカリ水酸化物および炭酸塩の希薄溶液には容易に溶解する。葉酸の水溶液は、熱に敏感で光および／またはリボフラビンの存在下で容易に分解し、したがって、溶液は、冷所に、光から防護して保存されるべきである。 Folic acid exists as a yellow or yellow-orange crystalline powder, is extremely insoluble in water, insoluble in alcohol, and easily dissolved in dilute solutions of alkali hydroxides and carbonates. An aqueous solution of folic acid is sensitive to heat and easily decomposes in the presence of light and / or riboflavin, and therefore the solution should be stored in a cool place protected from light.
よく知られているように、Ｂ複合体群のビタミンは、身体が炭水化物をグルコースに変換するのを助け、グルコースはエネルギーを生み出すために代謝される。これらのビタミンは、脂肪およびタンパク質の分解において必須であり、消化管内膜に沿う筋緊張の維持において、および神経系、皮膚、毛髪、眼、口および肝臓の健康の増進において重要な役割を果たす。 As is well known, the B complex family of vitamins helps the body convert carbohydrates into glucose, which is metabolized to produce energy. These vitamins are essential in the breakdown of fats and proteins and play an important role in maintaining muscle tone along the lining of the gastrointestinal tract and in promoting health of the nervous system, skin, hair, eyes, mouth and liver .
新規の細胞の産生および維持に葉酸が必須であることも知られている。乳幼児期や妊娠中などの迅速な細胞***および成長の期間において、このことは特に重要である。葉酸塩は、ＤＮＡの複製に必要である。したがって、葉酸塩が欠乏すると、ＤＮＡ合成および細胞***が阻害され、最も臨床的には、迅速な細胞交替の一部位である骨髄に影響を与える。ＲＮＡおよびタンパク質の合成は阻害されないので、大きい赤血球、すなわち、巨大赤芽球が産生され、巨大赤芽球貧血（セリアック病において見られ得るような）などの大球性貧血、および栄養起源のまたは妊娠中、乳幼児期もしくは小児期における貧血をもたらす。それゆえ、大人も子供も共に、正常な赤血球を産生し、貧血を防止するために葉酸塩を必要とする。葉酸塩はまた、がんへ導き得るＤＮＡへの変化を防止するのも助ける。 It is also known that folic acid is essential for the production and maintenance of new cells. This is particularly important during periods of rapid cell division and growth, such as infancy and pregnancy. Folate is required for DNA replication. Thus, deficiency in folate inhibits DNA synthesis and cell division and most clinically affects bone marrow, a site of rapid cell turnover. Since RNA and protein synthesis is not inhibited, large erythrocytes, i.e. giant erythroblasts, are produced, macrocytic anemia such as giant erythroblast anemia (as may be seen in celiac disease), and of nutritional origin or Causes anemia during pregnancy, infancy or childhood. Therefore, both adults and children produce normal red blood cells and require folate to prevent anemia. Folate also helps prevent changes to DNA that can lead to cancer.
多様なテトラヒドロ葉酸誘導体などの葉酸誘導体が、薬物としてまたは他の誘導体を調製するための基本物質として使用され得ることも知られている。しかし、テトラヒドロ葉酸およびこの誘導体は、特に、酸化に対するその感受性のために、極端な不安定性を有することも知られている。 It is also known that folic acid derivatives, such as various tetrahydrofolic acid derivatives, can be used as drugs or as basic materials for preparing other derivatives. However, tetrahydrofolic acid and its derivatives are also known to have extreme instability, especially due to their sensitivity to oxidation.
具体的には、５−メチルテトラヒドロ葉酸は、主として腫瘍学における薬物成分として、メトトレキサートおよび５−フルオロウラシル治療との併用療法として、ならびに妊娠、抗生物質療法等に伴う葉酸欠乏性貧血の治療において、重要性を有する。 Specifically, 5-methyltetrahydrofolate is important primarily as a drug component in oncology, as a combination therapy with methotrexate and 5-fluorouracil treatment, and in the treatment of folate deficiency anemia associated with pregnancy, antibiotic therapy, etc. Have sex.
葉酸塩および還元型葉酸塩の中では、最も比較的安定な誘導体としてカルシウム塩を挙げることができる。ＵＳ５，８１７，６５９およびＵＳ６，４４１，１６８は、該酸の１当量当たり少なくとも１当量の結晶水を有する、５−メチル−（６Ｒ，Ｓ）−、−（６Ｓ）−または−（６Ｒ）−のテトラヒドロ葉酸の結晶性塩、好ましくは、カルシウム塩を開示している。 Among folate and reduced folate, calcium salts can be mentioned as the most relatively stable derivatives. US 5,817,659 and US 6,441,168 have 5-methyl- (6R, S)-,-(6S)-or-(6R)-having at least one equivalent of crystal water per equivalent of the acid. Crystalline salts of tetrahydrofolic acid, preferably calcium salts.
５−メチルテトラヒドロ葉酸カルシウムは、それ以上代謝されることなく血液脳関門を直接透過し得る葉酸誘導体であって、市場に出されている唯一のものである。天然に存在する５−メチルテトラヒドロ葉酸は、もっぱらＳ型で存在し、Ｒ型は生化学的には不活性であり、腎臓を通して***される。 Calcium 5-methyltetrahydrofolate is the only folate derivative on the market that can penetrate the blood brain barrier directly without further metabolism. Naturally occurring 5-methyltetrahydrofolic acid exists exclusively in the S form, and the R form is biochemically inactive and is excreted through the kidney.
これらの塩は水に不溶であることが報告されている。さらに、葉酸塩および／または還元型葉酸塩のどちらかを含む、ヒトおよび動物による摂取のためのいくつかの組成物が、種々の形態でならびにビタミン、アルギニン、リジン、チアミン、および／またはその他の活性成分と共に、栄養補助剤として、または、例えば、神経性、病態心理学的、循環器疾患、関節炎および炎症状態などの種々の疾患の治療と予防のためのどちらかで、例えば、ＵＳ５８１７６５９、ＵＳ５，９９７，９１５、ＵＳ６，０９３，７０３、ＵＳ６，２４１，９９６、ＵＳ６，２５４，９０４、ＵＳ６，２６１，６００、ＵＳ６２７１３７４、ＵＳ６，４４０，４５０、ＵＳ６４４１１６８、ＵＳ６，４４４，２１８、ＵＳ６，４５１，３６０、ＵＳ６，５１４，９７３、ＵＳ６，５４４，９４４、ＵＳ６５９６７２１、ＵＳ６，６０５，６４６、ＵＳ６，６７３，３８１、ＵＳ６，８０８，７２５、ＵＳ６，９１４，０７３、ＵＳ６，９２１，７５４、ＵＳ６，９９５，１５８、ＵＳ２００２／００９４９７０、ＵＳ２００４／０２１９２６２、ＵＳ２００５／０１１３３３２、ＵＳ２００６／００６３７６８において開示されている。 These salts have been reported to be insoluble in water. In addition, several compositions for ingestion by humans and animals, including either folate and / or reduced folate, are available in various forms as well as vitamins, arginine, lysine, thiamine, and / or other With active ingredients, either as nutritional supplements or for the treatment and prevention of various diseases such as, for example, neurological, pathophysiological, cardiovascular disease, arthritis and inflammatory conditions, for example US Pat. No. 5,817,659, US5 , 997, 915, US 6,093,703, US 6,241,996, US 6,254,904, US 6,261,600, US 6271374, US 6,440,450, US 6441168, US 6,444,218, US 6,451,360 , US 6,514,973, US 6,544,944, US 65967 1, US 6,605,646, US 6,673,381, US 6,808,725, US 6,914,073, US 6,921,754, US 6,995,158, US 2002/0094970, US 2004/0219262, US 2005/0113332, US 2006/0063768.
したがって、いかなる特別な注意なしに、葉酸塩および／または還元型葉酸塩および／またはそのような化合物を含む組成物を医薬として使用可能にする望ましい水溶性と共により高い化学的安定性が、依然として必要とされている。 Thus, without any special attention, there is still a need for higher chemical stability with desirable water solubility that allows folate and / or reduced folate and / or compositions containing such compounds to be used as pharmaceuticals. It is said that.
本発明により、長期持続する安定性および特異的に高い水溶性が達成され得ることが、期せずして見出された。 It has been unexpectedly found that long-lasting stability and specifically high water solubility can be achieved with the present invention.
実際、第１の態様によれば、本発明は、Ｄ−グルコサミンおよびＤ−ガラクトサミンからなる群から選択された少なくとも１種の有機塩基の、置換もしくは非置換の葉酸塩もしくは還元型葉酸塩、またはその天然もしくは非天然の異性体である、結晶性または非晶性の化合物に関する。 Indeed, according to a first aspect, the present invention provides a substituted or unsubstituted folate or reduced folate of at least one organic base selected from the group consisting of D-glucosamine and D-galactosamine, or It relates to crystalline or amorphous compounds that are natural or non-natural isomers.
好ましくは、本発明の還元型葉酸塩は、（６Ｒ，Ｓ）、（６Ｓ）または（６Ｒ）配置を示し、特に、ジ−またはテトラヒドロ葉酸塩である。 Preferably, the reduced folate according to the invention exhibits a (6R, S), (6S) or (6R) configuration, in particular a di- or tetrahydrofolate.
本発明の葉酸塩および還元型葉酸塩は、好ましくは、非置換のまたは５−メチル−、５−ホルミル−、１０−ホルミル−、５，１０−メチレン−、５，１０−メテニル−部分によって置換されている、Ｄ−グルコサミン、Ｄ−ガラクトサミン、−葉酸塩、−ジヒドロ葉酸塩、−テトラヒドロ葉酸塩からなる群から選択され、該化合物は、考えられる場合は常に、（６Ｒ，Ｓ）、（６Ｓ）または（６Ｒ）配置である。 The folate and reduced folate of the invention are preferably unsubstituted or substituted by a 5-methyl-, 5-formyl-, 10-formyl-, 5,10-methylene-, 5,10-methenyl- moiety. Selected from the group consisting of D-glucosamine, D-galactosamine, -folate, -dihydrofolate, -tetrahydrofolate, which compounds are (6R, S), (6S) whenever possible. ) Or (6R) configuration.
より好ましくは、本発明の葉酸塩および還元型葉酸塩は、Ｄ−グルコサミン−葉酸塩、Ｄ−ガラクトサミン−葉酸塩、Ｄ−グルコサミン（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン（６Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン（６Ｒ）−テトラヒドロ葉酸塩；Ｄ−ガラクトサミン（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−ガラクトサミン（６Ｓ）−テトラヒドロ葉酸塩、Ｄ−ガラクトサミン（６Ｒ）−テトラヒドロ葉酸塩；Ｄ−グルコサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン５−メチル−（６Ｒ）−テトラヒドロ葉酸塩；Ｄ−ガラクトサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−ガラクトサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩、Ｄ−ガラクトサミン５−メチル−（６Ｒ）−テトラヒドロ葉酸塩からなる群から選択される。 More preferably, the folate and reduced folate of the present invention are D-glucosamine-folate, D-galactosamine-folate, D-glucosamine (6R, S) -tetrahydrofolate, D-glucosamine (6S)- Tetrahydrofolate, D-glucosamine (6R) -tetrahydrofolate; D-galactosamine (6R, S) -tetrahydrofolate, D-galactosamine (6S) -tetrahydrofolate, D-galactosamine (6R) -tetrahydrofolate; D-glucosamine 5-methyl- (6R, S) -tetrahydrofolate, D-glucosamine 5-methyl- (6S) -tetrahydrofolate, D-glucosamine 5-methyl- (6R) -tetrahydrofolate; D-galactosamine 5-Methyl- (6R, S) -tetrahydrofolate, D-galactosamine 5-methyl (6S) - tetrahydrofolate, D- galactosamine 5-methyl - is selected from the group consisting of tetrahydrofolate - (6R).
好ましい実施形態によれば、本発明の還元型葉酸塩は、（６Ｓ）配置である。 According to a preferred embodiment, the reduced folate of the present invention is in the (6S) configuration.
さらにより好ましくは、葉酸塩および還元型葉酸塩は、Ｄ−グルコサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン葉酸塩、Ｄ−ガラクトサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−ガラクトサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩、Ｄ−ガラクトサミン葉酸塩からなる群から選択される。 Even more preferably, the folate and reduced folate are D-glucosamine 5-methyl- (6R, S) -tetrahydrofolate, D-glucosamine 5-methyl- (6S) -tetrahydrofolate, D-glucosamine folate. The salt is selected from the group consisting of D-galactosamine 5-methyl- (6R, S) -tetrahydrofolate, D-galactosamine 5-methyl- (6S) -tetrahydrofolate, D-galactosamine folate.
Ｄ−グルコサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩、Ｄ−グルコサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩およびＤ−グルコサミン葉酸塩は、本発明の最も好ましい化合物である。 D-glucosamine 5-methyl- (6R, S) -tetrahydrofolate, D-glucosamine 5-methyl- (6S) -tetrahydrofolate and D-glucosamine folate are the most preferred compounds of the present invention.
本発明の化合物はまた、非晶性状態であることが好ましい。 The compounds of the invention are also preferably in an amorphous state.
「葉酸塩」という用語は一般に、当分野では、葉酸に構造的に関連していると同時に同様の生物学的活性を有するいくつかの化学的形態を総称的に意味するために使われるが、本明細書においては、一般に、置換または非置換の葉酸の塩、およびこの天然もしくは非天然の異性体の塩および／またはそれらの混合物の塩を指すが、一方で、「還元型葉酸塩」という用語は、一般に、置換または非置換のジヒドロ葉酸またはテトラヒドロ葉酸のいずれかの塩およびこの天然または非天然のいかなる異性体の塩をも指す。 The term “folate” is generally used in the art to generically mean several chemical forms that are structurally related to folic acid and have similar biological activity, As used herein, generally refers to salts of substituted or unsubstituted folic acid, and salts of this natural or non-natural isomer and / or mixtures thereof, while referred to as “reduced folate”. The term generally refers to salts of either substituted or unsubstituted dihydrofolate or tetrahydrofolate and any natural or non-natural isomeric salts thereof.
本発明の化合物は、並外れて長期持続する化学的安定性を示し、このことは、数カ月の後でも純度がまったく変化しないこと、および対応する葉酸塩または還元型葉酸塩部分の力価が実質的に不変であることを実際に保証する。 The compounds of the present invention exhibit an exceptionally long lasting chemical stability, indicating that there is no change in purity even after several months and that the titer of the corresponding folate or reduced folate moiety is substantial. To guarantee that it is immutable.
本発明の化合物のさらなる他の特異点は、本発明の化合物の葉酸塩および還元型葉酸塩の対イオン分子は、動物体内にすでに存在しており、自ずから明らかなように毒性を示さないことにある。 Yet another peculiarity of the compounds of the present invention is that the folate and reduced folate counterion molecules of the compounds of the present invention are already present in the animal body and, as is obvious, are not toxic. is there.
本発明のＤ−グルコサミンおよびＤ−ガラクトサミン化合物は、これらの並外れて高い化学的安定性の他に、驚くほど完全な水溶性（１ｇ／ｍｌよりもずっと高い）を示し、このことは、自ずから明らかなように、例えば、アルカリ塩およびカルシウム塩のようなアルカリ土類金属塩などのこれまでに知られている他の葉酸塩または還元型葉酸塩とは逆に、優れたバイオアベイラビリティーを意味することも注記され得る。 In addition to their exceptionally high chemical stability, the D-glucosamine and D-galactosamine compounds of the present invention exhibit surprisingly complete water solubility (much higher than 1 g / ml), which is clearly evident In contrast to other folates or reduced folates known so far, such as alkaline earth metal salts such as alkali salts and calcium salts, it means excellent bioavailability This can also be noted.
他の態様によれば、本発明は、少なくとも１種の本発明の化合物を含む組成物に関する。 According to another aspect, the present invention relates to a composition comprising at least one compound of the present invention.
当業者であれば当分野の共通の一般的な知識に基づいて理解するはずであるが、本発明の組成物は、種々の形態、固体（例えば、錠剤）または液体（例えば、液剤）のどちらでも、好ましくは、非経口および／または経口の医薬製剤の形態にも製剤化し得るし、他の不活性および／または活性成分をさらに含み得る。そのようなさらなる成分として、本発明の組成物は、またおよび好ましくは、以下の物質：ラクトース一水和物、結晶セルロース、デンプングリコール酸ナトリウム、ステアリン酸、ビタミン［特に、ビタミンＡ、Ｂ（Ｂ１、Ｂ２、Ｂ６、Ｂ１２）、Ｃ、アスコルビン酸、アスコルビン酸塩、Ｄ（Ｄ３）、Ｅ、Ｋ、ＰＰ］、アルギニン、リジン、チアミン、必須の、飽和もしくは不飽和のω−３および／またはω−６脂肪酸（好ましくは、ＤＨＡ、ＡＲＡ、ＥＰＡ）、ＳＡＭｅ、コバラミン、ユビキノン、プロバイオティクス（ラクトバシリ、芽胞、イースト）、リン脂質、セリン、コリン、イノシトール、エチレンジアミン、植物抽出物（ブルーベリー、ロイコシアニジン、銀杏、朝鮮人参、緑茶、バレリアン、トケイソウ、カモミール）、メラトニン、ミネラル、オリゴエレメント等のうちの少なくとも１種を含むことができ、症例が示す必要性および状況に応じて、その必要のある対象に対して有効量で投与され得る。 As those skilled in the art will appreciate based on common general knowledge in the art, the compositions of the present invention may be in various forms, either solid (eg, tablets) or liquid (eg, liquids). However, preferably it may also be formulated in the form of parenteral and / or oral pharmaceutical preparations and may further comprise other inert and / or active ingredients. As such a further component, the composition according to the invention also and preferably comprises the following substances: lactose monohydrate, crystalline cellulose, sodium starch glycolate, stearic acid, vitamins [in particular vitamins A, B (B1 B2, B6, B12), C, ascorbic acid, ascorbate, D (D3), E, K, PP], arginine, lysine, thiamine, essential, saturated or unsaturated ω-3 and / or ω. -6 fatty acids (preferably DHA, ARA, EPA), SAMe, cobalamin, ubiquinone, probiotics (lactobacilli, spore, yeast), phospholipid, serine, choline, inositol, ethylenediamine, plant extract (blueberry, leucocyanidine) , Ginkgo, ginseng, green tea, valerian, passiflora, chamomile), It can contain at least one of melatonin, minerals, oligoelements, etc. and can be administered in an effective amount to a subject in need thereof depending on the needs and circumstances indicated by the case.
単なる例示であるが、本発明の化合物および／または組成物は、対象の一日の葉酸必要量の、５から３０００％、より好ましくは、５から２００％を与える量で投与され得る。特に、用量は、１と２，０００μｇ／日の間、より好ましくは、１μｇと５００μｇの間、最も好ましくは、２０と２００μｇ／日の間、特には、１用量単位当たり５μｇから１５０μｇの間の量であり得る。 By way of example only, the compounds and / or compositions of the invention may be administered in an amount that provides 5 to 3000%, more preferably 5 to 200%, of the subject's daily folic acid requirement. In particular, the dose is between 1 and 2,000 μg / day, more preferably between 1 μg and 500 μg, most preferably between 20 and 200 μg / day, in particular between 5 μg and 150 μg per dose unit. It can be an amount.
他の態様によれば、本発明は、葉酸塩および還元型葉酸塩の両方の投与により確実に影響が与えられる欠乏または疾患のいずれかの予防および／または治療のための薬物、食品添加物または栄養補助剤の調製のための、上記に規定したように、本発明の、少なくとも１種の化合物および／または１種の組成物の使用を開示する。 According to another aspect, the present invention relates to a medicament, food additive or for the prevention and / or treatment of either a deficiency or disease reliably affected by the administration of both folate and reduced folate. Disclosed is the use of at least one compound and / or one composition of the invention as defined above for the preparation of a nutritional supplement.
単なる例示であるが、上記に規定したように、本発明の化合物および／または組成物は、例えば、認知症および空胞性脊髄症に伴う亜急性脳炎などの神経疾患；例えば、早発性閉塞性動脈疾患、乳幼児期および小児期における重症な血管疾患、進行性動脈狭窄、間欠性跛行、腎血管性高血圧、虚血性脳血管障害、早発性網膜動脈および網膜静脈閉塞、大脳閉塞性動脈疾患、閉塞性末梢動脈疾患、血栓塞栓性疾患および／または虚血性心疾患による早発性死亡などの病態心理学的、血管および循環器疾患；例えば、乾癬、セリアック病、関節炎および炎症状態などの自己免疫疾患；葉酸塩欠乏のための巨大赤芽球貧血、腸吸収障害、流産することおよび／または神経管欠陥、***裂欠陥および／または口蓋裂欠陥を有する胎児を有するという女性のリスク低減のため、ホモシステインレベルおよび／または代謝を維持および／または正常化するため；ＤＮＡおよびＲＮＡの合成および／または機能化および／または変化を変更させることならびに細胞合成を変更させること；うつ病の予防および／または治療のための薬物、食品添加物または栄養補助剤の調製のために、使用され得る。 By way of example only, as defined above, the compounds and / or compositions of the present invention may be used in neurological diseases such as, for example, subacute encephalitis associated with dementia and vacuolar myelopathy; Arterial disease, severe vascular disease in infancy and childhood, progressive arterial stenosis, intermittent claudication, renovascular hypertension, ischemic cerebrovascular disorder, premature retinal artery and retinal vein occlusion, cerebral occlusive arterial disease, Pathopsychological, vascular and cardiovascular diseases such as premature death from obstructive peripheral arterial disease, thromboembolic disease and / or ischemic heart disease; eg autoimmunity such as psoriasis, celiac disease, arthritis and inflammatory conditions Disease; woman with giant erythroblast anemia due to folate deficiency, intestinal malabsorption, miscarriage and / or fetus with neural tube defects, cleft lip and / or cleft palate defects To maintain and / or normalize homocysteine levels and / or metabolism; to alter DNA and RNA synthesis and / or functionalization and / or changes and to alter cell synthesis; It can be used for the preparation of drugs, food additives or nutritional supplements for the prevention and / or treatment of diseases.
本発明の化合物は、当業者であれば容易に理解するように、当分野の一般的な知識を単純に適用することにより調製され得るが、非制限的な例として、本発明の化合物は、好ましくは、窒素雰囲気下で攪拌しながら、塩基を酸に対してモル比で約２００から３００％で、Ｄ−グルコサミンまたはＤ−ガラクトサミンを含む水溶液に所望の置換または非置換の葉酸または還元型葉酸を加えることにより調製され得る。 The compounds of the invention can be prepared by simple application of general knowledge in the art, as will be readily appreciated by those skilled in the art, but as a non-limiting example, the compounds of the invention Preferably, the desired substituted or unsubstituted folic acid or reduced folic acid is added to an aqueous solution containing D-glucosamine or D-galactosamine in a molar ratio of about 200 to 300% with respect to the acid while stirring under a nitrogen atmosphere. Can be prepared.
結果として、所望の酸は完全に溶解され、それにより、約６．３と８．０の間のｐＨを有する、所望の葉酸塩または還元型葉酸塩を含む均一で透明な溶液が得られる。 As a result, the desired acid is completely dissolved, thereby obtaining a uniform, clear solution containing the desired or reduced folate having a pH between about 6.3 and 8.0.
モル比２００％で、所望の置換または非置換の葉酸塩または還元型葉酸塩とＤ−グルコサミンまたはＤ−ガラクトサミンとから得られる塩は、完全に水溶性であり、当業者であれば直ちに理解できるように、例えば当分野の共通の一般的な知識を単純に適用することにより、および別法として、得られた所望の葉酸塩または還元型葉酸塩の溶液を直接凍結乾燥することにより、または得られた所望の葉酸塩または還元型葉酸塩の溶液を噴霧乾燥することにより、自ずから明らかなように、容易に集められ得る。 The salt obtained from the desired substituted or unsubstituted folate or reduced folate and D-glucosamine or D-galactosamine at a molar ratio of 200% is completely water soluble and can be readily understood by those skilled in the art. Thus, for example, by simply applying common general knowledge in the field and, alternatively, by directly lyophilizing or obtaining the desired folate or reduced folate solution obtained or obtained By spray drying a solution of the desired folate or reduced folate obtained, it can be easily collected as is obvious.
実施される回収法に関係なく、本発明の所望の葉酸塩または還元型葉酸塩がほぼ定量的な量で得られることは有利な点として注目され得る。 Regardless of the recovery method carried out, it can be noted as an advantage that the desired folate or reduced folate according to the invention is obtained in approximately quantitative amounts.
以下の実施例は、制限することなく、本発明を例示する。 The following examples illustrate the invention without limiting it.
Ｄ−グルコサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩の調製
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸４．６０ｇ（１０ｍｍｏｌ）を少しずつ加え、窒素雰囲気下で攪拌されたＤ−グルコサミン（３．５８ｇ、２０ｍｍｏｌ）の水溶液３０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を凍結乾燥して、８．７２ｇの標題生成物を得た。
Preparation of D-glucosamine 5-methyl- (6R, S) -tetrahydrofolate 4.60 g (10 mmol) of 5-methyl- (6R, S) -tetrahydrofolic acid was added little by little, and D- stirred under a nitrogen atmosphere. It was completely dissolved in 30 ml of an aqueous solution of glucosamine (3.58 g, 20 mmol). The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.
分析データ：
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸中のＨＰＬＣ力価：計算値５６．１８％（乾燥生成物基準で）；測定値５５．２２％（理論値の９８．３％）；
比旋光度［α］２０ Ｄ＝＋５４．２°（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：７．４５（ｄ，２Ｈ）；６．５５（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．０５（ｍ，Ｈ）；３．７０−３．４０（ｍ，７Ｈ）；３．３８−３．００（ｍ，６Ｈ）；２．９９−２．７０（ｍ，４Ｈ）；２．４０（ｓ，３Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in 5-methyl- (6R, S) -tetrahydrofolic acid: calculated 56.18% (on dry product basis); measured 55.22% (98.3% of theory);
Specific rotation [α] 20 D = + 54.2 ° (C = 1 in water)
NMR (D 2 O): 7.45 (d, 2H); 6.55 (d, 2H); 5.20 (bs, 2H); 4.05 (m, H); 3.70-3.40 (M, 7H); 3.38-3.00 (m, 6H); 2.99-2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m , 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).
Ｄ−グルコサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩の調製
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸９．１９ｇ（２０ｍｍｏｌ）を少しずつ加え、窒素雰囲気下で攪拌されたＤ−グルコサミン（７．１２ｇ、４０ｍｍｏｌ）の水溶液６０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を噴霧乾燥して、１６．９ｇの標題生成物を得た。
Preparation of D-glucosamine 5-methyl- (6R, S) -tetrahydrofolate 9.19 g (20 mmol) of 5-methyl- (6R, S) -tetrahydrofolic acid was added little by little, and D- stirred under a nitrogen atmosphere. It was completely dissolved in 60 ml of an aqueous solution of glucosamine (7.12 g, 40 mmol). The resulting solution (pH 6.53) was spray dried to give 16.9 g of the title product.
分析データ：
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸中のＨＰＬＣ力価：計算値５６．１８％（乾燥生成物基準で）；測定値５５．１３（理論値の９８．２％）；
比旋光度［α］２０ Ｄ＝＋５４．０（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：７．４５（ｄ，２Ｈ）；６．５５（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．０５（ｍ，Ｈ）；３．７０−３．４０（ｍ，７Ｈ）；３．３８−３．００（ｍ，６Ｈ）；２．９９−２．７０（ｍ，４Ｈ）；２．４０（ｓ，３Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in 5-methyl- (6R, S) -tetrahydrofolic acid: Calculated 56.18% (on dry product basis); Found 55.13 (98.2% of theory);
Specific rotation [α] 20 D = + 54.0 (C = 1 in water)
NMR (D 2 O): 7.45 (d, 2H); 6.55 (d, 2H); 5.20 (bs, 2H); 4.05 (m, H); 3.70-3.40 (M, 7H); 3.38-3.00 (m, 6H); 2.99-2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m , 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).
Ｄ−グルコサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩の調製
対応する（６Ｒ，Ｓ）−５−メチルテトラヒドロ葉酸を分離して得た５−メチル−（６Ｓ）−テトラヒドロ葉酸４．６０ｇ（１０ｍｍｏｌ）を少しずつ加えて、窒素雰囲気下で攪拌されたＤ−グルコサミン（３．５８ｇ、２０ｍｍｏｌ）の水溶液３０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を凍結乾燥して、８．７２ｇの標題生成物を得た。
Preparation of D-glucosamine 5-methyl- (6S) -tetrahydrofolate 4.60 g (10 mmol) of 5-methyl- (6S) -tetrahydrofolate obtained by separating the corresponding (6R, S) -5-methyltetrahydrofolate ) Was added little by little and completely dissolved in 30 ml of an aqueous solution of D-glucosamine (3.58 g, 20 mmol) stirred under a nitrogen atmosphere. The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.
分析データ：
５−メチル−（６Ｓ）−テトラヒドロ葉酸中のＨＰＬＣ力価：計算値５６．１８％（乾燥生成物基準で）；測定値５５．７％（理論値の９９．１％）；
比旋光度［α］２０ Ｄ＝＋４２．６°（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：７．４５（ｄ，２Ｈ）；６．５５（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．０５（ｍ，Ｈ）；３．７０−３．４０（ｍ，７Ｈ）；３．３８−３．００（ｍ，６Ｈ）；２．９９−２．７０（ｍ，４Ｈ）；２．４０（ｓ，３Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in 5-methyl- (6S) -tetrahydrofolic acid: calculated value 56.18% (based on dry product); measured value 55.7% (99.1% of theory);
Specific rotation [α] 20 D = + 42.6 ° (C = 1 in water)
NMR (D 2 O): 7.45 (d, 2H); 6.55 (d, 2H); 5.20 (bs, 2H); 4.05 (m, H); 3.70-3.40 (M, 7H); 3.38-3.00 (m, 6H); 2.99-2.70 (m, 4H); 2.40 (s, 3H); 2.15-2.05 (m , 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).
Ｄ−グルコサミンＬ−葉酸塩の調製
Ｌ−葉酸４．４１ｇ（１０ｍｍｏｌ）を少しずつ加えて、窒素雰囲気下で攪拌されたＤ−グルコサミン（３．５８ｇ、２０ｍｍｏｌ）の水溶液４０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を凍結乾燥して、７．９５ｇの標題生成物を得た。
Preparation of D-glucosamine L-folate 4.41 g (10 mmol) of L-folic acid was added little by little and completely dissolved in 40 ml of an aqueous solution of D-glucosamine (3.58 g, 20 mmol) stirred under a nitrogen atmosphere. The resulting solution (pH 6.53) was lyophilized to give 7.95 g of the title product.
分析データ：
Ｌ−葉酸中のＨＰＬＣ力価：計算値５５．２％（乾燥生成物基準で）；測定値５４．６（理論値の９９．０％）；
比旋光度［α］２０ Ｄ＝＋４４．５°（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：８．４２（ｓ，１Ｈ）；７．４５（ｄ，２Ｈ）；６．４２（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．２５（ｓ，２Ｈ）；４．０５（ｍ，１Ｈ）；３．７５−３．４５（ｍ，６Ｈ）；３．３５−３．２０（ｍ，２Ｈ）；３．１５−３．００（ｍ，２Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in L-folic acid: calculated 55.2% (on dry product basis); measured 54.6 (99.0% of theory);
Specific rotation [α] 20 D = + 44.5 ° (C = 1 in water)
NMR (D 2 O): 8.42 (s, 1H); 7.45 (d, 2H); 6.42 (d, 2H); 5.20 (bs, 2H); 4.25 (s, 2H) 4.05 (m, 1H); 3.75-3.45 (m, 6H); 3.35-3.20 (m, 2H); 3.15-3.00 (m, 2H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).
Ｄ−ガラクトサミン５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸塩の調製
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸４．６０ｇ（１０ｍｍｏｌ）を少しずつ加えて、窒素雰囲気下で攪拌されたＤ−ガラクトサミン（３．５８ｇ、２０ｍｍｏｌ）の水溶液３０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を凍結乾燥して、８．７２ｇの標題生成物を得た。
Preparation of D-galactosamine 5-methyl- (6R, S) -tetrahydrofolate 4.60 g (10 mmol) of 5-methyl- (6R, S) -tetrahydrofolic acid was added in portions and stirred under a nitrogen atmosphere. -Completely dissolved in 30 ml of an aqueous solution of galactosamine (3.58 g, 20 mmol). The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.
分析データ：
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸中のＨＰＬＣ力価：計算値５６．１８％（乾燥生成物基準で）；測定値５５．５％（理論値の９８．８％）；
比旋光度［α］２０ Ｄ＝＋５１．４３°（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：７．４５（ｄ，２Ｈ）；６．５５（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．１５（ｍ，Ｈ）；３．７０−３．３５（ｍ，７Ｈ）；３．３０−２．８５（ｍ，１０Ｈ）；２．４０（ｓ，３Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in 5-methyl- (6R, S) -tetrahydrofolic acid: Calculated 56.18% (on dry product basis); Found 55.5% (98.8% of theory);
Specific rotation [α] 20 D = + 51.43 ° (C = 1 in water)
NMR (D 2 O): 7.45 (d, 2H); 6.55 (d, 2H); 5.20 (bs, 2H); 4.15 (m, H); 3.70-3.35 (M, 7H); 3.30-2.85 (m, 10H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m , 1H); 1.90-1.75 (m, 1H).
Ｄ−ガラクトサミン５−メチル−（６Ｓ）−テトラヒドロ葉酸塩の調製
対応する（６Ｒ，Ｓ）−５−メチルテトラヒドロ葉酸を分離して得た５−メチル−（６Ｓ）−テトラヒドロ葉酸４．６０ｇ（１０ｍｍｏｌ）を少しずつ加えて、窒素雰囲気下で攪拌されたＤ−ガラクトサミン（３．５８ｇ、２０ｍｍｏｌ）の水溶液３０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を凍結乾燥して、８．７２ｇの標題生成物を得た。
Preparation of D-galactosamine 5-methyl- (6S) -tetrahydrofolate 4.60 g (10 mmol) of 5-methyl- (6S) -tetrahydrofolate obtained by separating the corresponding (6R, S) -5-methyltetrahydrofolate ) Was added little by little and completely dissolved in 30 ml of an aqueous solution of D-galactosamine (3.58 g, 20 mmol) stirred under a nitrogen atmosphere. The resulting solution (pH 6.53) was lyophilized to give 8.72 g of the title product.
分析データ：
５−メチル−（６Ｒ，Ｓ）−テトラヒドロ葉酸中のＨＰＬＣ力価：計算値５６．１８％（乾燥生成物基準で）；測定値５５．５％（理論値の９８．８％）；
比旋光度［α］２０ Ｄ＝＋６６．５°（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：７．４５（ｄ，２Ｈ）；６．５５（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．１５（ｍ，Ｈ）；３．７０−３．３５（ｍ，７Ｈ）；３．３０−２．８５（ｍ，１０Ｈ）；２．４０（ｓ，３Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in 5-methyl- (6R, S) -tetrahydrofolic acid: Calculated 56.18% (on dry product basis); Found 55.5% (98.8% of theory);
Specific rotation [α] 20 D = + 66.5 ° (C = 1 in water)
NMR (D 2 O): 7.45 (d, 2H); 6.55 (d, 2H); 5.20 (bs, 2H); 4.15 (m, H); 3.70-3.35 (M, 7H); 3.30-2.85 (m, 10H); 2.40 (s, 3H); 2.15-2.05 (m, 2H); 2.05-1.90 (m , 1H); 1.90-1.75 (m, 1H).
Ｄ−ガラクトサミンＬ−葉酸塩の調製
Ｌ−葉酸４．４１ｇ（１０ｍｍｏｌ）を少しずつ加えて、窒素雰囲気下で攪拌されたＤ−ガラクトサミン（３．５８ｇ、２０ｍｍｏｌ）の水溶液４０ｍｌに完全に溶解した。得られた溶液（ｐＨ６．５３）を凍結乾燥して、７．９５ｇの標題生成物を得た。
Preparation of D-galactosamine L-folate 4.41 g (10 mmol) of L-folic acid was added little by little and completely dissolved in 40 ml of an aqueous solution of D-galactosamine (3.58 g, 20 mmol) stirred under a nitrogen atmosphere. The resulting solution (pH 6.53) was lyophilized to give 7.95 g of the title product.
分析データ：
Ｌ−葉酸中のＨＰＬＣ力価：計算値５５．２％（乾燥生成物基準で）；測定値５４．７（理論値の９９．１％）；
比旋光度［α］２０ Ｄ＝＋４９．７７（Ｃ＝１水中）
ＮＭＲ（Ｄ２Ｏ）：８．４２（ｓ，１Ｈ）；７．４５（ｄ，２Ｈ）；６．４２（ｄ，２Ｈ）；５．２０（ｂｓ，２Ｈ）；４．２５（ｓ，２Ｈ）；４．０５（ｍ，１Ｈ）；３．７５−３．４５（ｍ，６Ｈ）；３．３５−３．２０（ｍ，２Ｈ）；３．１５−３．００（ｍ，２Ｈ）；２．１５−２．０５（ｍ，２Ｈ）；２．０５−１．９０（ｍ，１Ｈ）；１．９０−１．７５（ｍ，１Ｈ）。
Analysis data:
HPLC titer in L-folic acid: calculated 55.2% (on dry product basis); measured 54.7 (99.1% of theory);
Specific rotation [α] 20 D = + 49.77 (C = 1 in water)
NMR (D 2 O): 8.42 (s, 1H); 7.45 (d, 2H); 6.42 (d, 2H); 5.20 (bs, 2H); 4.25 (s, 2H) 4.05 (m, 1H); 3.75-3.45 (m, 6H); 3.35-3.20 (m, 2H); 3.15-3.00 (m, 2H); 2.15-2.05 (m, 2H); 2.05-1.90 (m, 1H); 1.90-1.75 (m, 1H).
安定性
下表に記載した化合物の安定性について、粉末形態で、封をしたアルミホイル袋の中に入れ、遮光された密閉容器中にサンプルを保存し、６および１２カ月後に、純度と力価を測定して試験した。
Stability For the stability of the compounds listed in the table below, place the sample in powder form in a sealed aluminum foil bag, store the sample in a light-tight sealed container, and after 6 and 12 months purity and titer. Were measured and tested.
比較として、結晶性（６Ｒ，Ｓ）−、（６Ｓ）−および（６Ｒ）−テトラヒドロ葉酸カルシウム塩は、ＵＳ５，８１７，６５９（実施例１）に開示されているように、９カ月後に力価が約２％減少した一方、ＵＳ６，２７１，３７４（実施例１）に報告されているように、結晶性（６Ｓ）−および（６Ｒ）−テトラヒドロ葉酸カルシウム塩では、そのような減少が１２カ月後に約７％に達したことは注目され得る。結晶性５−メチル−（６Ｓ）−テトラヒドロ葉酸カルシウム塩に関しては、ＵＳ６，４４１，１６８（実施例１）は、代わりに、１２カ月後の力価減少は約１％に達したと報告している。 By way of comparison, crystalline (6R, S)-, (6S)-and (6R) -tetrahydrofolic acid calcium salts have titers after 9 months as disclosed in US 5,817,659 (Example 1). Decreased by about 2%, while crystalline (6S)-and (6R) -tetrahydrofolate calcium salts, as reported in US Pat. No. 6,271,374 (Example 1), showed a decrease of 12 months. It can be noted that later about 7% was reached. For crystalline 5-methyl- (6S) -tetrahydrofolate calcium salt, US 6,441,168 (Example 1) reports instead that the titer reduction after 12 months has reached about 1%. Yes.
上記の表に示されたデータからみて、本発明の化合物に関しては、安全に１２カ月の有効期限を設定でき、１２カ月後の力価減少は１％未満であることがさらに注目される。上記の表に記載の化合物はどれも高い安定性を示し、これらの純度および力価の両方とも１２カ月後でも、要求仕様内に十分入る結果を与えた。特に、純度およびその力価を検出して、酸部分の安定性がＨＰＬＣにより観測された。 In view of the data presented in the above table, it is further noted that for the compounds of the present invention, an expiration date of 12 months can be safely set and the titer decrease after 12 months is less than 1%. All of the compounds listed in the table above showed high stability, and both their purity and titer gave results that were well within the required specifications even after 12 months. In particular, purity and its titer were detected and the stability of the acid moiety was observed by HPLC.
バイオアベイラビリティー
体重２００−３００ｇのマウス１２匹で、以下に報告するように、選択された化合物の用量をラクトースに分散して含む３ｍｇのカプセル１個をマウスのそれぞれに投与して生物学的試験を行った。
Bioavailability Biological studies in 12 mice weighing 200-300 g, each with one 3 mg capsule containing a dose of the selected compound dispersed in lactose as reported below Went.
次いで、選択された化合物の造血値を、定期的な時間間隔（０、３０、６０、９５、１２０分）後に評価した。 The hematopoietic values of selected compounds were then evaluated after regular time intervals (0, 30, 60, 95, 120 minutes).
以下の化合物、Ｄ−グルコサミン葉酸塩（６０μｇ）、Ｄ−グルコサミン［６Ｒ，Ｓ］５−メチルテトラヒドロ葉酸塩（６１μｇ）、Ｄ−グルコサミン［６Ｓ］５−メチルテトラヒドロ葉酸塩（６１μｇ）、Ｄ−ガラクトサミン葉酸塩（６０μｇ）、Ｄ−ガラクトサミン［６Ｒ，Ｓ］５−メチルテトラヒドロ葉酸塩（６１μｇ）、Ｄ−ガラクトサミン［６Ｓ］−５−メチルテトラヒドロ葉酸塩（６１μｇ）を試験し、以下のもの、非晶性葉酸カルシウム塩（３８μｇ）、非晶性［６Ｒ，Ｓ］−５−メチルテトラヒドロ葉酸カルシウム塩（３９μｇ）、非晶性［６Ｓ］−５−メチルテトラヒドロ葉酸カルシウム塩（３９μｇ）、結晶性葉酸カルシウム塩（３９μｇ）、結晶性［６Ｒ，Ｓ］−５−メチルテトラヒドロ葉酸カルシウム塩（３９μｇ）、結晶性［６Ｓ］−５−メチルテトラヒドロ葉酸カルシウム塩（３９μｇ）と比較した。 The following compounds, D-glucosamine folate (60 μg), D-glucosamine [6R, S] 5-methyltetrahydrofolate (61 μg), D-glucosamine [6S] 5-methyltetrahydrofolate (61 μg), D-galactosamine Folate (60 μg), D-galactosamine [6R, S] 5-methyltetrahydrofolate (61 μg), D-galactosamine [6S] -5-methyltetrahydrofolate (61 μg) were tested and the following, amorphous Crystalline calcium folate (38 μg), amorphous [6R, S] -5-methyltetrahydrofolic acid calcium salt (39 μg), amorphous [6S] -5-methyltetrahydrofolic acid calcium salt (39 μg), crystalline calcium folate Salt (39 μg), crystalline [6R, S] -5-methyltetrahydrofolate calcium salt (39 μg), crystals Comparison with sex [6S] -5-methyltetrahydrofolate calcium salt (39 μg).
生物学的な試験は、本発明の化合物を投与することにより、対応する葉酸塩および還元型葉酸塩のカルシウム塩の同様な用量を動物に投与した時に見出される値よりも、造血レベルが約２０％高い結果を与えることを示した。 Biological tests have shown that by administering a compound of the present invention, the level of hematopoiesis is about 20 greater than the value found when similar doses of the corresponding folate and reduced folate calcium salts are administered to animals. % Gave higher results.
さらに、非晶性のカルシウム塩を投与することにより、結晶性のカルシウム塩に比べて、以下の表で例示されているように、バイオアベイラビリティーがわずかではあるが有意に増加（約１０％）することが注目された。 In addition, administration of amorphous calcium salt resulted in a slight but significant increase in bioavailability (about 10%) compared to crystalline calcium salt, as illustrated in the table below. It was noticed to do.
したがって、本発明のＤ−グルコサミンおよびＤ−ガラクトサミン化合物の高水溶性が、いかにして確実におよび有意にそれらの吸収に影響を及ぼし、それによりすべての分子の活性部分のバイオアベイラビリティーを増強していることが明らかである。 Thus, the high water solubility of the D-glucosamine and D-galactosamine compounds of the present invention reliably and significantly affects their absorption, thereby enhancing the bioavailability of the active portion of all molecules. It is clear that
Claims (21)
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| US11690846B2 (en) | 2017-09-29 | 2023-07-04 | Aprofol Ag | Folate salts for medical use |
| JP2021529206A (en) * | 2018-07-06 | 2021-10-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | Crystalline salt containing 5-methyl (6S) -tetrahydrofolic acid and 4- (2-hydroxyethyl) -morpholine |
| JP2021530466A (en) * | 2018-07-06 | 2021-11-11 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Crystalline salts of 5-methyl- (6S) -tetrahydrofolic acid and L-isoleucine ethyl ester |
| JP2022506246A (en) * | 2018-10-31 | 2022-01-17 | アプロフォル アクチェンゲゼルシャフト | Folic acid salt |
Also Published As
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| AU2008351242B2 (en) | 2012-12-20 |
| CA2712714A1 (en) | 2009-08-27 |
| ZA201005278B (en) | 2011-09-28 |
| MX2010009075A (en) | 2010-11-26 |
| PT2245032E (en) | 2015-07-21 |
| BRPI0822337A2 (en) | 2015-06-16 |
| PL2245032T3 (en) | 2015-08-31 |
| NZ586959A (en) | 2012-04-27 |
| EP2245032B1 (en) | 2015-03-25 |
| ES2538480T3 (en) | 2015-06-22 |
| CN101970439A (en) | 2011-02-09 |
| KR101512624B1 (en) | 2015-04-16 |
| UA103310C2 (en) | 2013-10-10 |
| IL207164A (en) | 2015-01-29 |
| HRP20150674T1 (en) | 2015-07-31 |
| AU2008351242A2 (en) | 2010-09-09 |
| KR20110011602A (en) | 2011-02-08 |
| WO2009103334A1 (en) | 2009-08-27 |
| BRPI0822337B1 (en) | 2019-02-12 |
| IL207164A0 (en) | 2010-12-30 |
| HUE025450T2 (en) | 2016-04-28 |
| SI2245032T1 (en) | 2015-08-31 |
| EA201070966A1 (en) | 2011-02-28 |
| BRPI0822337B8 (en) | 2021-05-25 |
| CN101970439B (en) | 2014-11-12 |
| AU2008351242A1 (en) | 2009-08-27 |
| CA2712714C (en) | 2015-05-12 |
| EA017742B1 (en) | 2013-02-28 |
| DK2245032T3 (en) | 2015-06-22 |
| EP2245032A1 (en) | 2010-11-03 |
| JP5856372B2 (en) | 2016-02-09 |
| CY1116343T1 (en) | 2017-02-08 |
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